TY - JOUR T1 - Biotransformation of prasugrel, a novel thienopyridine antiplatelet agent, to the pharmacologically active metabolite JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.110.032086 SP - dmd.110.032086 AU - Katsunobu Hagihara AU - Miho Kazui AU - Atsushi Kurihara AU - Haruo Iwabuchi AU - Minoru Ishikawa AU - Hiroyuki Kobayashi AU - Naoki Tanaka AU - Osamu Okazaki AU - Nagy A. Farid AU - Toshihiko Ikeda Y1 - 2010/01/01 UR - http://dmd.aspetjournals.org/content/early/2010/03/12/dmd.110.032086.abstract N2 - Prasugrel, a novel thienopyridine antiplatelet agent, undergoes rapid hydrolysis in vivo to a thiolactone, R-95913, which is further converted to its a thiol-containing, pharmacologically active metabolite, R-138727, by oxidation via cytochromes P450. We trapped a sulfenic acid metabolite as a mixed disulfide with 2-nitro-5-thiobenzoic acid (TNB) in an incubation mixture containing the thiolactone R-95913, expressed CYP3A4 and NADPH. Further experiments investigated one possible mechanism for the conversion of the sulfenic acid to the active thiol metabolite in vitro. A mixed disulfide form of R-138727 with glutathione was found to be a possible precursor of R-138727 in vitro when glutathione was present. The rate constant for the reduction of the glutathione conjugate of R-138727 to R-138727 was increased by addition of human liver cytosol to the human liver microsomes. Thus, one possible mechanism for the ultimate formation of R-138727 in vitro can be through formation of a sulfenic acid mediated by CYPs followed possibly by a glutathione conjugation to a mixed disulfide and reduction of the disulfide to the active metabolite R-138727.The American Society for Pharmacology and Experimental Therapeutics ER -